The portrayal of the history of medicine becomes more difficult in the 19th century. Discoveries multiply, and the number of eminent doctors is so great that the history is apt to become a series of biographies. Nevertheless, it is possible to discern the leading trends in modern medical thought.

Physiology

By the beginning of the 19th century, the structure of the human body was almost fully known, due to new methods of microscopy and of injections. Even the body’s microscopic structure was understood. But as important as anatomical knowledge was an understanding of physiological processes, which were rapidly being elucidated, especially in Germany. There, physiology became established as a distinct science under the guidance of Johannes Müller, who was a professor at Bonn and then at the University of Berlin. An energetic worker and an inspiring teacher, he described his discoveries in a famous textbook, Handbuch der Physiologie des Menschen (“Manual of Human Physiology”), published in the 1830s.

Among Müller’s illustrious pupils were Hermann von Helmholtz, who made significant discoveries relating to sight and hearing and who invented the ophthalmoscope; and Rudolf Virchow, one of the century’s great medical scientists, whose outstanding achievement was his conception of the cell as the centre of all pathological changes. Virchow’s work Die Cellularpathologie, published in 1858, gave the deathblow to the outmoded view that disease is due to an imbalance of the four humours.

In France the most brilliant physiologist of the time was Claude Bernard, whose many important discoveries were the outcome of carefully planned experiments. His researches clarified the role of the pancreas in digestion, revealed the presence of glycogen in the liver, and explained how the contraction and expansion of the blood vessels are controlled by vasomotor nerves. He proposed the concept of the internal environment—the chemical balance in and around the cells—and the importance of its stability. His Introduction à l’étude de la médecine expérimentale (1865; An Introduction to the Study of Experimental Medicine) is still worthy of study by all who undertake research.

Verification of the germ theory

Perhaps the overarching medical advance of the 19th century, certainly the most spectacular, was the conclusive demonstration that certain diseases, as well as the infection of surgical wounds, were directly caused by minute living organisms. This discovery changed the whole face of pathology and effected a complete revolution in the practice of surgery.

The idea that disease was caused by entry into the body of imperceptible particles was of ancient date. It had been expressed by the Roman encyclopaedist Varro as early as 100 BC, by Fracastoro in 1546, by Athanasius Kircher and Pierre Borel about a century later, and by Francesco Redi, who in 1684 wrote his Osservazioni intorno agli animali viventi che si trovano negli animali viventi (“Observations on Living Animals Which Are to Be Found Within Other Living Animals”), in which he sought to disprove the idea of spontaneous generation. Everything must have a parent, he wrote; only life produces life. A 19th-century pioneer in this field, regarded by some as founder of the parasitic theory of infection, was Agostino Bassi of Italy, who showed that a disease of silkworms was caused by a fungus that could be destroyed by chemical agents.

The main credit for establishing the science of bacteriology must be accorded to the French chemist Louis Pasteur. It was Pasteur who, by a brilliant series of experiments, proved that the fermentation of wine and the souring of milk are caused by living microorganisms. His work led to the pasteurization of milk and solved problems of agriculture and industry as well as those of animal and human diseases. He successfully employed inoculations to prevent anthrax in sheep and cattle, chicken cholera in fowl, and finally rabies in humans and dogs. The latter resulted in the widespread establishment of Pasteur institutes.

From Pasteur, Joseph Lister derived the concepts that enabled him to introduce the antiseptic principle into surgery. In 1865 Lister, a professor of surgery at Glasgow University, began placing an antiseptic barrier of carbolic acid between the wound and the germ-containing atmosphere. Infections and deaths fell dramatically, and his pioneering work led to more refined techniques of sterilizing the surgical environment.

Obstetrics had already been robbed of some of its terrors by Alexander Gordon at Aberdeen, Scot., Oliver Wendell Holmes at Boston, and Ignaz Semmelweis at Vienna and Pest (Budapest), who advocated disinfection of the hands and clothing of midwives and medical students who attended confinements. These measures produced a marked reduction in cases of puerperal fever, the bacterial scourge of women following childbirth.

Another pioneer in bacteriology was the German physician Robert Koch, who showed how bacteria could be cultivated, isolated, and examined in the laboratory. A meticulous investigator, Koch discovered the organisms of tuberculosis, in 1882, and cholera, in 1883. By the end of the century many other disease-producing microorganisms had been identified.

Discoveries in clinical medicine and anesthesia

There was perhaps some danger that in the search for bacteria other causes of disease would escape detection. Many physicians, however, were working along different lines in the 19th century. Among them were a group attached to Guy’s Hospital, in London: Richard Bright, Thomas Addison, and Sir William Gull. Bright contributed significantly to the knowledge of kidney diseases, including Bright’s disease, and Addison gave his name to disorders of the adrenal glands and the blood. Gull, a famous clinical teacher, left a legacy of pithy aphorisms that might well rank with those of Hippocrates.

In Dublin Robert Graves and William Stokes introduced new methods in clinical diagnosis and medical training; while in Paris a leading clinician, Pierre-Charles-Alexandre Louis, was attracting many students from America by the excellence of his teaching. By the early 19th century the United States was ready to send back the results of its own researches and breakthroughs. In 1809, in a small Kentucky town, Ephraim McDowell boldly operated on a woman—without anesthesia or antisepsis—and successfully removed a large ovarian tumour. William Beaumont, in treating a shotgun wound of the stomach, was led to make many original observations that were published in 1833 as Experiments and Observations on the Gastric Juice and the Physiology of Digestion.

The most famous contribution by the United States to medical progress at this period was undoubtedly the introduction of general anesthesia, a procedure that not only liberated the patient from the fearful pain of surgery but also enabled the surgeon to perform more extensive operations. The discovery was marred by controversy. Crawford Long, Gardner Colton, Horace Wells, and Charles Jackson are all claimants for priority; some used nitrous oxide gas, and others employed ether, which was less capricious. There is little doubt, however, that it was William Thomas Morton who, on Oct. 16, 1846, at Massachusetts General Hospital, in Boston, first demonstrated before a gathering of physicians the use of ether as a general anesthetic. The news quickly reached Europe, and general anesthesia soon became prevalent in surgery. At Edinburgh, the professor of midwifery, James Young Simpson, had been experimenting upon himself and his assistants, inhaling various vapours with the object of discovering an effective anesthetic. In November 1847 chloroform was tried with complete success, and soon it was preferred to ether and became the anesthetic of choice.

Advances at the end of the century

While antisepsis and anesthesia placed surgery on an entirely new footing, similarly important work was carried out in other fields of study, such as parasitology and disease transmission. Patrick Manson, a British pioneer in tropical medicine, showed in China, in 1877, how insects can carry disease and how the embryos of the Filaria worm, which can cause elephantiasis, are transmitted by the mosquito. Manson explained his views to a British army surgeon, Ronald Ross, then working on the problem of malaria, and Ross discovered the malarial parasite in the stomach of the Anopheles mosquito in 1897.

In Cuba, Carlos Finlay expressed the view, in 1881, that yellow fever is carried by the Stegomyia mosquito. Following his lead, the Americans Walter Reed, William Gorgas, and others were able to conquer the scourge of yellow fever in Panama and made possible the completion of the Panama Canal by reducing the death rate there from 176 per 1,000 to 6 per 1,000.

Other victories in preventive medicine ensued, because the maintenance of health was now becoming as important a concern as the cure of disease; and the 20th century was to witness the evolution and progress of national health services in a number of countries. In addition, spectacular advances in diagnosis and treatment followed the discovery of X rays by Wilhelm Conrad Röntgen, in 1895, and of radium by Pierre and Marie Curie in 1898. Before the turn of the century, too, the vast new field of psychiatry had been opened up by Sigmund Freud. The tremendous increase in scientific knowledge during the 19th century radically altered and expanded the practice of medicine. Concern for upholding the quality of services led to the establishment of public and professional bodies to govern the standards for medical training and practice.

Medicine in the 20th century

The 20th century has produced such a plethora of discoveries and advances that in some ways the face of medicine has changed out of all recognition. In 1901, for instance, in the United Kingdom the expectation of life at birth, a primary indicator of the effect of health care on mortality (but also reflecting the state of health education, housing, and nutrition), was 48 years for males and 51.6 years for females. After steady increases, by the 1980s life expectancy had reached 71.4 years for males and 77.2 years for females. Other industrialized nations showed similar dramatic increases. Indeed, the outlook has so altered that, with the exception of diseases such as cancer and AIDS, attention has become focused on morbidity rather than mortality, and the emphasis has changed from keeping people alive to keeping them fit.

The rapid progress of medicine in this era was reinforced by enormous improvements in communication between scientists throughout the world. Through publications, conferences, and—later—computers and electronic media, they freely exchanged ideas and reported on their endeavours. No longer was it common for an individual to work in isolation. Although specialization increased, teamwork became the norm. It consequently has become more difficult to ascribe medical accomplishments to particular individuals.

In the first half of the century, emphasis continued to be placed on combating infection, and notable landmarks were also attained in endocrinology, nutrition, and other areas. In the years following World War II, insights derived from cell biology altered basic concepts of the disease process; new discoveries in biochemistry and physiology opened the way for more precise diagnostic tests and more effective therapies; and spectacular advances in biomedical engineering enabled the physician and surgeon to probe into the structures and functions of the body by noninvasive imaging techniques like ultrasound (sonar), computerized axial tomography (CAT), and nuclear magnetic resonance (NMR). With each new scientific development, medical practices of just a few years earlier became obsolete.

Infectious diseases and chemotherapy

In the years following the turn of the century, ongoing research concentrated on the nature of infectious diseases and their means of transmission. Increasing numbers of pathogenic organisms were discovered and classified. Some, such as the rickettsias, which cause diseases like typhus, were smaller than bacteria; some were larger, such as the protozoans that engender malaria and other tropical diseases. The smallest to be identified were the viruses, producers of many diseases, among them mumps, measles, German measles, and poliomyelitis; and in 1910 Peyton Rous showed that a virus could also cause a malignant tumour, a sarcoma in chickens.

There was still little to be done for the victims of most infectious organisms beyond drainage, poultices, and ointments, in the case of local infections, and rest and nourishment for severe diseases. The search for treatments aimed at both vaccines and chemical remedies.

Ehrlich and arsphenamine

Germany was well to the forefront in medical progress. The scientific approach to medicine had been developed there long before it spread to other countries, and postgraduates flocked to German medical schools from all over the world. The opening decade of the 20th century has been well described as the golden age of German medicine. Outstanding among its leaders was Paul Ehrlich.

While still a student, Ehrlich carried out some work on lead poisoning from which he evolved the theory that was to guide much of his subsequent work—that certain tissues have a selective affinity for certain chemicals. He experimented with the effects of various chemical substances on disease organisms. In 1910, with his colleague Sahachiro Hata, he conducted tests on arsphenamine, once sold under the commercial name Salvarsan. Their success inaugurated the chemotherapeutic era, which was to revolutionize the treatment and control of infectious diseases. Salvarsan, a synthetic preparation containing arsenic, is lethal to the microorganism responsible for syphilis. Until the introduction of penicillin, Salvarsan or one of its modifications remained the standard treatment of syphilis and went far toward bringing this social and medical scourge under control.

Sulfonamide drugs

In 1932 the German bacteriologist Gerhard Domagk announced that the red dye Prontosil is active against streptococcal infections in mice and humans. Soon afterward French workers showed that its active antibacterial agent is sulfanilamide. In 1936 the English physician Leonard Colebrook and his colleagues provided overwhelming evidence of the efficacy of both Prontosil and sulfanilamide in streptococcal septicemia (bloodstream infection), thereby ushering in the sulfonamide era. New sulfonamides, which appeared with astonishing rapidity, had greater potency, wider antibacterial range, or lower toxicity. Some stood the test of time; others, like the original sulfanilamide and its immediate successor, sulfapyridine, were replaced by safer and more powerful successors.

Antibiotics

Penicillin

A dramatic episode in medical history occurred in 1928, when Alexander Fleming noticed the inhibitory action of a stray mold on a plate culture of staphylococcus bacteria in his laboratory at St. Mary’s Hospital, London. Many other bacteriologists must have made the observation, but none had realized the possible implications. The mold was a strain of Penicillium—P. notatum—which gave its name to the now-famous drug penicillin. In spite of his conviction that penicillin was a potent antibacterial agent, Fleming was unable to carry his work to fruition, mainly because biochemists at the time were unable to isolate it in sufficient quantities or in a sufficiently pure form to allow its use on patients.

Ten years later Howard Florey, Ernst Chain, and their colleagues at Oxford University took up the problem again They isolated penicillin in a form that was fairly pure (by standards then current) and demonstrated its potency and relative lack of toxicity. By then World War II had begun, and techniques to facilitate commercial production were developed in the United States. By 1944 adequate amounts were available to meet the extraordinary needs of wartime.

Antituberculous drugs

While penicillin is the most useful and the safest antibiotic, it suffers from certain disadvantages. The most important of these is that it is not active against Mycobacterium tuberculosis, the bacillus of tuberculosis. In view of the importance of tuberculosis as a public health hazard, this is a serious defect. The position was rapidly rectified when, in 1944, Selman Waksman, Albert Schatz, and Elizabeth Bugie announced the discovery of streptomycin from cultures of a soil organism, Streptomyces griseus, and stated that it was active against M. tuberculosis. Subsequent clinical trials amply confirmed this claim. Streptomycin suffers, however, from the great disadvantage that the tubercle bacillus tends to become resistant to it. Fortunately, other drugs became available to supplement it, the two most important being para-aminosalicylic acid (PAS) and isoniazid. With a combination of two or more of these preparations, the outlook in tuberculosis improved immeasurably. The disease was not conquered, but it was brought well under control.

Other antibiotics

Penicillin is not effective over the entire field of microorganisms pathogenic to humans. During the 1950s the search for antibiotics to fill this gap resulted in a steady stream of them, some with a much wider antibacterial range than penicillin (the so-called broad-spectrum antibiotics) and some capable of coping with those microorganisms that are inherently resistant to penicillin or that have developed resistance through exposure to penicillin.

This tendency of microorganisms to develop resistance to penicillin at one time threatened to become almost as serious a problem as the development of resistance to streptomycin by the bacillus of tuberculosis. Fortunately, early appreciation of the problem by clinicians resulted in more discriminate use of penicillin. Scientists continued to look for means of obtaining new varieties of penicillin, and their researches produced the so-called semisynthetic antibiotics, some of which are active when taken by mouth, while others are effective against microorganisms that have developed resistance to the earlier form of penicillin.

Immunology

Dramatic though they undoubtedly were, the advances in chemotherapy still left one important area vulnerable, that of the viruses. It was in bringing viruses under control that advances in immunology—the study of immunity—played such a striking part. One of the paradoxes of medicine is that the first large-scale immunization against a viral disease was instituted and established long before viruses were discovered. When Edward Jenner introduced vaccination against the virus that causes smallpox, the identification of viruses was still 100 years in the future. It took almost another half century to discover an effective method of producing antiviral vaccines that were both safe and effective.

In the meantime, however, the process by which the body reacts against infectious organisms to generate immunity became better understood. In Paris, Élie Metchnikoff had already detected the role of white blood cells in the immune reaction, and Jules Bordet had identified antibodies in the blood serum. The mechanisms of antibody activity were used to devise diagnostic tests for a number of diseases. In 1906 August von Wassermann gave his name to the blood test for syphilis, and in 1908 the tuberculin test—the skin test for tuberculosis—came into use. At the same time, methods of producing effective substances for inoculation were improved, and immunization against bacterial diseases made rapid progress.

Antibacterial vaccination

Typhoid

In 1897 the English bacteriologist Almroth Wright introduced a vaccine prepared from killed typhoid bacilli as a preventive of typhoid. Preliminary trials in the Indian army produced excellent results, and typhoid vaccination was adopted for the use of British troops serving in the South African War. Unfortunately, the method of administration was inadequately controlled, and the government sanctioned inoculations only for soldiers that “voluntarily presented themselves for this purpose prior to their embarkation for the seat of war.” The result was that, according to the official records, only 14,626 men volunteered out of a total strength of 328,244 who served during the three years of the war. Although later analysis showed that inoculation had had a beneficial effect, there were 57,684 cases of typhoid—approximately one in six of the British troops engaged—with 9,022 deaths.

A bitter controversy over the merits of the vaccine followed, but before the outbreak of World War I immunization had been officially adopted by the army. Comparative statistics would seem to provide striking confirmation of the value of antityphoid inoculation, even allowing for the better sanitary arrangements in the latter war. In the South African War the annual incidence of enteric infections (typhoid and paratyphoid) was 105 per 1,000 troops, and the annual death rate was 14.6 per 1,000; the comparable figures for World War I were 2.35 and 0.139, respectively.

It is perhaps a sign of the increasingly critical outlook that developed in medicine in the post-1945 era that experts continued to differ on some aspects of typhoid immunization. There was no question as to its fundamental efficacy, but there was considerable variation of opinion as to the best vaccine to use and the most effective way of administering it. Moreover, it was often difficult to decide to what extent the decline in typhoid was attributable to improved sanitary conditions and what to the greater use of the vaccine.

Tetanus

The other great hazard of war that was brought under control in World War I was tetanus. This was achieved by the prophylactic injection of tetanus antitoxin into all wounded men. The serum was originally prepared by the bacteriologists Emil von Behring and Shibasaburo Kitasato in 1890–92, and the results of this first large-scale trial amply confirmed its efficacy. (Tetanus antitoxin is a sterile solution of antibody globulins—a type of blood protein—from immunized horses or cattle.)

It was not until the 1930s, however, that an efficient vaccine, or toxoid, as it is known in the cases of tetanus and diphtheria, was produced against tetanus. (Tetanus toxoid is a preparation of the toxin—or poison—produced by the microorganism; injected into humans, it stimulates the body’s own defenses against the disease, thus bringing about immunity.) Again, a war was to provide the opportunity for testing on a large scale, and experience with tetanus toxoid in World War II indicated that it gave a high degree of protection.

Diphtheria

The story of diphtheria is comparable to that of tetanus, though even more dramatic. First, as with tetanus antitoxin, came the preparation of diphtheria antitoxin by Behring and Kitasato in 1890. As the antitoxin came into general use for the treatment of cases, the death rate began to decline. There was no significant fall in the number of cases, however, until a toxin–antitoxin mixture, introduced by Behring in 1913, was used to immunize children. A more effective toxoid was introduced by the French bacteriologist Gaston Ramon in 1923, and with subsequent improvements this became one of the most effective vaccines available in medicine. Where mass immunization of children with the toxoid was practiced, as in the United States and Canada beginning in the late 1930s and in England and Wales in the early 1940s, cases of diphtheria and deaths from the disease became almost nonexistent. In England and Wales, for instance, the number of deaths fell from an annual average of 1,830 in 1940–44 to zero in 1969. Administration of a combined vaccine against diphtheria, pertussis (whooping cough), and tetanus (DPT) is recommended for young children. Although an increasing number of dangerous side effects from the DPT vaccine have been reported, it continues to be used in most countries because of the protection it affords.

BCG vaccine for tuberculosis

If, as is universally accepted, prevention is better than cure, immunization is the ideal way of dealing with diseases caused by microorganisms. An effective, safe vaccine protects the individual from disease, whereas chemotherapy merely copes with the infection once the individual has been affected. In spite of its undoubted value, however, immunization has been a recurring source of dispute. Like vaccination against typhoid (and against poliomyelitis later), tuberculosis immunization evoked widespread contention.

In 1908 Albert Calmette, a pupil of Pasteur, and Camille Guérin produced an avirulent (weakened) strain of the tubercle bacillus. About 13 years later, vaccination of children against tuberculosis was introduced, with a vaccine made from this avirulent strain and known as BCG (bacillus Calmette-Guérin) vaccine. Although it was adopted in France, Scandinavia, and elsewhere, British and U.S. authorities frowned upon its use on the grounds that it was not safe and that the statistical evidence in its favour was not convincing.

One of the stumbling blocks in the way of its widespread adoption was what came to be known as the Lübeck disaster. In the spring of 1930, 249 infants were vaccinated with BCG vaccine in Lübeck, Ger.; by autumn, 73 of the 249 were dead. Criminal proceedings were instituted against those responsible for giving the vaccine. The final verdict was that the vaccine had been contaminated, and the BCG vaccine itself was exonerated from any responsibility for the deaths. A bitter controversy followed, but in the end the protagonists of the vaccine won when a further trial showed that the vaccine was safe and that it protected four out of five of those vaccinated.

Immunization against viral diseases

With the exception of smallpox, it was not until well into the 20th century that efficient viral vaccines became available. In fact, it was not until the 1930s that much began to be known about viruses. The two developments that contributed most to the rapid growth in knowledge after that time were the introduction of tissue culture as a means of growing viruses in the laboratory and the availability of the electron microscope. Once the virus could be cultivated with comparative ease in the laboratory, the research worker could study it with care and evolve methods for producing one of the two requirements for a safe and effective vaccine: either a virus that was so attenuated, or weakened, that it could not produce the disease for which it was responsible in its normally virulent form; or a killed virus that retained the faculty of inducing a protective antibody response in the vaccinated individual.

The first of the viral vaccines to result from these advances was for yellow fever, developed by the microbiologist Max Theiler in the late 1930s. About 1945 the first relatively effective vaccine was produced for influenza; in 1954 the American physician Jonas E. Salk introduced a vaccine for poliomyelitis; and in 1960 an oral poliomyelitis vaccine, developed by the virologist Albert B. Sabin, came into wide use.

These vaccines went far toward bringing under control three of the major diseases of the time although, in the case of influenza, a major complication is the disturbing proclivity of the virus to change its character from one epidemic to another. Even so, sufficient progress has been made to ensure that a pandemic like the one that swept the world in 1918–19, killing more than 15,000,000 people, is unlikely to occur again. Centres are now equipped to monitor outbreaks of influenza throughout the world in order to establish the identity of the responsible viruses and, if necessary, take steps to produce appropriate vaccines.

During the 1960s effective vaccines came into use for measles and rubella (German measles). Both evoked a certain amount of controversy. In the case of measles in the Western world it was contended that, if acquired in childhood, it is not a particularly hazardous malady, and the naturally acquired disease evokes permanent immunity in the vast majority of cases. Conversely, the vaccine induces a certain number of adverse reactions, and the duration of the immunity it produces is problematical. In the end the official view was that universal measles vaccination is to be commended.

The situation with rubella vaccination was different. This is a fundamentally mild affliction, and the only cause for anxiety is its proclivity to induce congenital deformities if a pregnant woman should acquire the disease. Once an effective vaccine was available, the problem was the extent to which it should be used. Ultimately the consensus was reached that all girls who had not already had the disease should be vaccinated at about 12 years. In the United States children are routinely immunized against measles, mumps, and rubella at the age of 15 months.

The immune response

With advances in cell biology in the second half of the 20th century came a more profound understanding of both normal and abnormal conditions in the body. Electron microscopy enabled observers to peer more deeply into the structures of the cell, and chemical investigations revealed clues to their functions in the cell’s intricate metabolism. The overriding importance of the nuclear genetic material DNA (deoxyribonucleic acid) in regulating the cell’s protein and enzyme production lines became evident. A clearer comprehension also emerged of the ways in which the cells of the body defend themselves by modifying their chemical activities to produce antibodies against injurious agents.

Up until the turn of the century, immunity referred mostly to the means of resistance of an animal to invasion by a parasite or microorganism. Around mid-century there arose a growing realization that immunity and immunology cover a much wider field and are concerned with mechanisms for preserving the integrity of the individual. The introduction of organ transplantation, with its dreaded complication of tissue rejection, brought this broader concept of immunology to the fore.

At the same time, research workers and clinicians began to appreciate the far-reaching implications of immunity in relation to endocrinology, genetics, tumour biology, and the biology of a number of other maladies. The so-called autoimmune diseases are caused by an aberrant series of immune responses by which the body’s own cells are attacked. Suspicion is growing that a number of major disorders such as diabetes, rheumatoid arthritis, and multiple sclerosis may be caused by similar mechanisms.

In some conditions viruses invade the genetic material of cells and distort their metabolic processes. Such viruses may lie dormant for many years before becoming active. This may be the underlying cause of many cancers, in which cells escape from the usual constraints imposed upon them by the normal body. The dreaded affliction of acquired immune deficiency syndrome (AIDS) is caused by a virus that has a long dormant period and then attacks the cells that produce antibodies. The result is that the affected person is not able to generate an immune response to infections or malignancies.

Endocrinology

At the beginning of the 20th century, endocrinology was in its infancy. Indeed, it was not until 1905 that Ernest H. Starling, one of the many brilliant pupils of Edward Sharpey-Schafer, the dean of British physiology during the early decades of the century, introduced the term hormone for the internal secretions of the endocrine glands. In 1891 the English physician George Redmayne Murray achieved the first success in treating myxedema (the common form of hypothyroidism) with an extract of the thyroid gland. Three years later, Sharpey-Schafer and George Oliver demonstrated in extracts of the adrenal glands a substance that raised the blood pressure; and in 1901 Jokichi Takamine, a Japanese chemist working in the United States, isolated this active principle, known as epinephrine or adrenaline.

Insulin

During the first two decades of the century, steady progress was made in the isolation, identification, and study of the active principles of the various endocrine glands, but the outstanding event of the early years was the discovery of insulinby Frederick Banting, Charles H. Best, and . In 1921 Romanian physiologist Nicolas C. Paulescu reported the discovery of a substance called pancrein, now thought to have been insulin, in pancreatic extracts from dogs. Paulescu found that diabetic dogs given an injection of unpurified pancrein experienced a temporary decrease in blood glucose levels. Also in 1921, working independently of Paulescu, Canadian physician Frederick Banting and American-born Canadian physician Charles H. Best isolated insulin. They then worked with Canadian chemist James B. Collip and Scottish physiologist J.J.R. Macleod in 1921. to purify the substance. The following year a 14-year-old boy with severe diabetes was the first person to be treated successfully with the pancreatic extracts. Almost overnight the lot of the diabetic patient changed from a sentence of almost certain death to a prospect not only of survival but of a long and healthy life.

For more than 30 years, some of the greatest minds in physiology had been seeking the cause of diabetes mellitus. In 1889 the German physicians Joseph von Mering and Oskar Minkowski had shown that removal of the pancreas in dogs produced the disease. In 1901 the American pathologist Eugene L. Opie described degenerative changes in the clumps of cells in the pancreas known as the islets of Langerhans, thus confirming the association between failure in the function of these cells and diabetes. Sharpey-Schafer concluded that the islets of Langerhans secrete a substance that controls the metabolism of carbohydrate. Then Banting, Best, and Macleod, working at the University of Toronto, succeeded in isolating the elusive hormone and gave it the name insulin.

Insulin was available in a variety of forms, but synthesis on a commercial scale was not achieved, and the only source of the hormone was the pancreas of animals. One of its practical disadvantages is that it has to be given by injection; consequently an intense search was conducted for some alternative substance that would be active when taken by mouth. Various preparations—oral hypoglycemic agents, as they are known—appeared that were effective to a certain extent in controlling diabetes, but evidence indicated that these were only of value in relatively mild cases of the disease. For the person with advanced diabetes, a normal, healthy life remained dependent upon the continuing use of insulin injections.

Cortisone

Another major advance in endocrinology came from the Mayo Clinic, in Rochester, Minn. In 1949 Philip S. Hench and his colleagues announced that a substance isolated from the cortex of the adrenal gland had a dramatic effect upon rheumatoid arthritis. This was compound E, or cortisone, as it came to be known, which had been isolated by Edward C. Kendall in 1935. Cortisone and its many derivatives proved to be potent as anti-inflammatory agents. Although it is not a cure for rheumatoid arthritis, as a temporary measure cortisone can often control the acute exacerbation caused by the disease and can provide relief in other conditions, such as acute rheumatic fever, certain kidney diseases, certain serious diseases of the skin, and some allergic conditions, including acute exacerbations of asthma. Of even more long-term importance is the valuable role it has as a research tool.

Sex hormones

Not the least of the advances in endocrinology was the increasing knowledge and understanding of the sex hormones. This culminated in the application of this knowledge to the problem of birth control. After an initial stage of hesitancy, the contraceptive pill, with its basic rationale of preventing ovulation, was accepted by the vast majority of family-planning organizations and many gynecologists as the most satisfactory method of contraception. Its risks, practical and theoretical, introduced a note of caution, but this was not sufficient to detract from the wide appeal induced by its effectiveness and ease of use.

Vitamins

In the field of nutrition, the outstanding advance of the 20th century was the discovery and the appreciation of the importance to health of the “accessory food factors,” or vitamins. Various workers had shown that animals did not thrive on a synthetic diet containing all the correct amounts of protein, fat, and carbohydrate; they even suggested that there must be some unknown ingredients in natural food that were essential for growth and the maintenance of health. But little progress was made in this field until the classical experiments of the English biologist F. Gowland Hopkins were published in 1912. These were so conclusive that there could be no doubt that what he termed “accessory substances” were essential for health and growth.

The name vitamine was suggested for these substances by the biochemist Casimir Funk in the belief that they were amines, certain compounds derived from ammonia. In due course, when it was realized that they were not amines, the term was altered to vitamin.

Once the concept of vitamins was established on a firm scientific basis it was not long before their identity began to be revealed. Soon there was a long series of vitamins, best known by the letters of the alphabet after which they were originally named when their chemical identity was still unknown. By supplementing the diet with foods containing particular vitamins, deficiency diseases such as rickets (due to deficiency of vitamin D) and scurvy (due to lack of vitamin C, or ascorbic acid) practically disappeared from Western countries, while deficiency diseases such as beriberi (caused by lack of vitamin B1, or thiamine), which were endemic in Eastern countries, either disappeared or could be remedied with the greatest of ease.

The isolation of vitamin B12, or cyanocobalamin, was of particular interest because it almost rounded off the fascinating story of how pernicious anemia was brought under control. Throughout the first two decades of the century, the diagnosis of pernicious anemia, like that of diabetes mellitus, was nearly equivalent to a death sentence. Unlike the more common form of so-called secondary anemia, it did not respond to the administration of suitable iron salts, and no other form of treatment touched it; hence, the grimly appropriate title of pernicious anemia.

In the early 1920s, George R. Minot, one of the many brilliant investigators that Harvard University has contributed to medical research, became interested in work being done by the American pathologist George H. Whipple on the beneficial effects of raw beef liver in severe experimental anemia. With a Harvard colleague, William P. Murphy, he decided to investigate the effect of raw liver in patients with pernicious anemia, and in 1926 they were able to announce that this form of therapy was successful. The validity of their findings was amply confirmed, and the fear of pernicious anemia came to an end.

As so often happens in medicine, many years were to pass before the rationale of liver therapy in pernicious anemia was fully understood. In 1948, however, almost simultaneously in the United States and Britain, the active principle, cyanocobalamin, was isolated from liver, and this vitamin became the standard treatment for pernicious anemia.

Malignant disease

While progress was the hallmark of medicine after the beginning of the 20th century, there is one field in which a gloomier picture must be painted, that of malignant disease, or cancer. It is the second most common cause of death in most Western countries in the second half of the 20th century, being exceeded only by deaths from heart disease. Some progress, however, has been achieved. The causes of the various types of malignancies are not known, but many more methods are available for attacking the problem; surgery remains the principal therapeutic standby, but radiotherapy and chemotherapy are increasingly used.

Soon after the discovery of radium was announced, in 1898, its potentialities in treating cancer were realized; in due course it assumed an important role in therapy. Simultaneously, deep X-ray therapy was developed, and with the atomic age came the use of radioactive isotopes. (A radioactive isotope is an unstable variant of a substance that has a stable form; during the process of breaking down, the unstable form emits radiation.) High-voltage X-ray therapy and radioactive isotopes have largely replaced radium. Whereas irradiation long depended upon X rays generated at 250 kilovolts, machines that are capable of producing X rays generated at 8,000 kilovolts and betatrons of up to 22,000,000 electron volts (MeV) have come into clinical use.

The most effective of the isotopes is radioactive cobalt. Telecobalt machines (those that hold the cobalt at a distance from the body) are available containing 2,000 curies or more of the isotope, an amount equivalent to 3,000 grams of radium and sending out a beam equivalent to that from a 3,000-kilovolt X-ray machine.

Of even more significance have been the developments in the chemotherapy of cancer. Nothing remotely resembling a chemotherapeutic cure has been achieved, but in certain forms of malignant disease, such as leukemia, which cannot be treated by surgery, palliative effects have been achieved that prolong life and allow the patient in many instances to lead a comparatively normal existence.

Fundamentally, however, perhaps the most important advance of all in this field has been the increasing appreciation of the importance of prevention. The discovery of the relationship between cigarette smoking and lung cancer is the classic example. Less publicized, but of equal import, is the continuing supervision of new techniques in industry and food manufacture in an attempt to ensure that they do not involve the use of cancer-causing substances.

Tropical medicine

The first half of the 20th century witnessed the virtual conquest of three of the major diseases of the tropics: malaria, yellow fever, and leprosy. At the turn of the century, as for the preceding two centuries, quinine was the only known drug to have any appreciable effect on malaria. With the increasing development of tropical countries and rising standards of public health, it became obvious that quinine was not completely satisfactory. Intensive research between World Wars I and II indicated that several synthetic compounds were more effective. The first of these to become available, in 1934, was quinacrine (known as mepacrine, Atabrine, or Atebrin). In World War II it amply fulfilled the highest expectations and helped to reduce disease among Allied troops in Africa, Southeast Asia, and the Far East. A number of other effective antimalarial drugs subsequently became available.

An even brighter prospect—the virtual eradication of malaria—was opened up by the introduction, during World War II, of the insecticide DDT (1,1,1-trichloro-2,2,-bis[p-chlorophenyl]ethane, or dichlorodiphenyltrichloro-ethane). It had long been realized that the only effective way of controlling malaria was to eradicate the anopheline mosquitoes that transmit the disease. Older methods of mosquito control, however, were cumbersome and expensive. The lethal effect of DDT on the mosquito, its relative cheapness, and its ease of use on a widespread scale provided the answer. An intensive worldwide campaign, sponsored by the World Health Organization, was planned and went far toward bringing malaria under control.

The major problem encountered with respect to effectiveness was that the mosquitoes were able to develop a resistance to DDT; but the introduction of other insecticides, such as dieldrin and lindane (BHC), helped to overcome this difficulty. In recent years the use of these and other insecticides has been strongly criticized by ecologists, however.

Yellow fever is another mosquito-transmitted disease, and the prophylactic value of modern insecticides in its control was almost as great as in the case of malaria. The forest reservoirs of the virus present a more difficult problem, but the combined use of immunization and insecticides did much to bring this disease under control.

Until the 1940s the only drugs available for treating leprosy were the chaulmoogra oils and their derivatives. These, though helpful, were far from satisfactory. In the 1940s the group of drugs known as the sulfones appeared, and it soon became apparent that they were infinitely better than any other group of drugs in the treatment of leprosy. Several other drugs later proved promising. Although there is as yet no known cure—in the strict sense of the term—for leprosy, the outlook has so changed that there are good grounds for believing that this age-old scourge can be brought under control and the victims of the disease saved from those dreaded mutilations that have given leprosy such a fearsome reputation throughout the ages.